The overall goal of this proposal is to better understand the potential for increasing ?-cell PKA activity to enhance ?-cell function and improve glucose homeostasis in an aged population. In the elderly, a general decline in ?-cell function is often prominent and is typically manifested in an impairment in insulin secretion. Recently, new therapeutic agents aimed at enhancing??-cell insulin secretion by increasing intracellular cAMP levels have emerged. Protein kinase A (PKA) is one of two pathways that is activated by increases in ?-cell intracellular cAMP, and has a fundamental role in potentiating glucose stimulated insulin secretion in the ?-cell. The exclusive role of ?-cell PKA signaling and its effects on physiological glucose homeostasis remains unknown. We have created a novel transgenic mouse model harboring a constitutively active PKA in ?-cells that displays a three-fold enhancement in insulin secretion and improved glucose clearance. The proposed research will: [1] define the sustainability and efficacy of increased ?-cell PKA activity for improving ?-cell function, glucose control, and insulin sensitivity throughout aging, and [2] determine whether tighter glucose control leads to the maintenance of better insulin sensitivity even in an environment when glucose intolerance is heighted as observed in aged individuals and individuals with T2DM. The hypotheses that will be tested are: increased ?-cell PKA activity will [1] enhance first phase insulin secretion and improve glucose clearance throughout aging and maintain efficacy in aged individuals, and this will lead to [2] improved peripheral sensitivity with age. The second set of hypotheses that will be tested are: [1] induction of PKA activity will delay and/or prevent the progression towards high fat diet induced insulin resistance due to improved glucose homeostasis and better maintenance of??-cell mass; and [2] that PKA activation, after the establishment of insulin resistance, will lead to a recovery of glucose tolerance. Experimental techniques use physiological studies including fed and fasting glucose and insulin measurements, intraperitoneal glucose tolerance test, hyperglycemic and hyperinsulinemic-euglycemic clamp studies, and immunohistochemistry. A high-fat diet will be used to exacerbate insulin resistance. The results of this work will provide fundamental knowledge of??-cell PKA signaling and its potential as a therapeutic to improve b-cell function in the elderly. PUBLIC HEALTH RELEVANCE: Older individuals are predisposed to develop diabetes due to a decrease in the capacity of their pancreatic ?- cells to secrete sufficient insulin. The proposed studies will determine whether increased PKA signaling in ?- cells will improve ?-cell function and insulin secretory capacity in an aged population.